Background <p>Thalassemia is a genetic hemoglobin disorder commonly associated with iron overload and cardiac complications from repeated transfusions. Deferiprone (DFP), an oral iron chelator, has shown potential in reducing body iron and improving cardiac function. This systematic review and meta-analysis evaluates the efficacy and safety of DFP in thalassemia patients.</p> Methods <p>A systematic search of PubMed, MEDLINE, and Scopus was conducted from inception to June 8, 2025. Eligible randomized controlled trials (RCTs) enrolled thalassemia patients receiving iron chelation therapy and compared DFP (alone or in combination) with deferoxamine, deferasirox, placebo, or no chelation. Non-randomized studies, those without comparators, or lacking sufficient data were excluded. Risk of bias was assessed using the Cochrane RoB 2 tool, and certainty of evidence by GRADE. Pooled standardized mean differences (SMDs) the inclusion criteria; 18 were included in the meta-analysis. DFP significantly improved left ventricular ejection -effects model.</p> Results <p>Twenty-three RCTs (<i>n</i> = 1,005) met the inclusion criteria; 18 were included in the meta-analysis. DFP significantly improved left ventricular ejection fraction (SMD: 0.55) and shortening fraction (SMD: 0.37). Non-significant improvements were observed in urinary iron excretion and right ventricular ejection fraction. No significant effects were found for serum ferritin, liver iron concentration, or cardiac T2* MRI. DFP increased the risk of adverse events (RR: 1.37), but not mortality (RR: 0.30). Evidence certainty was moderate for cardiac function and adverse events, and low for other outcomes.</p> Conclusion <p>DFP improves cardiac function and iron excretion with an acceptable safety profile in thalassemia. Further high-quality RCTs are warranted to confirm its role and optimize regimens.</p> Systematic review registration <p>PROSPERO CRD420251028324.</p>